A number of cancers are associated with gene fusions. Perhaps the earliest reported example is the association of BCR-ABL with chronic myelogenous leukemia (CML) in the '60s (Nowell and Hungerford (1960) J. Natl. Cancer Inst. 25:85). Since then, hundreds more gene fusions have been reported for cancers in many different tissues (Presner and Chinnaiyan (2009) Curr. Opin Genet. Dev. 19:82).
Another example is the tyrosine receptor kinase ALK, EML4-ALK (echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase) fusions are associated with non-small cell lung cancer (NSCLC). In this case, the N terminal, extracellular portion of ALK is replaced by EML4 (KIF5B, HIP1, KLC1, TFG can also fuse with ALK in a similar manner). The expression of the resulting fusion gene is driven by the strong EML4 promoter, resulting in higher expression of the intracellular tyrosine kinase domain of ALK. In addition, EML4 forms a coiled-coil that results in ligand-independent dimerization, and constitutive activation of the ALK tyrosine kinase domain.
Detection of a gene fusion is important for directing therapy. Most current methods of detection require biopsy of tumor tissue, which is not feasible for many cancer patients, especially in later stages. Detection in biopsied tissue sections is typically carried out by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC). The tests have high false positive rates and background, in part because of shearing during the sectioning process. Skilled cytologists are thus required to observe multiple tissue sections, which necessitates a sizable biopsy from a weakened patient. Detection of fusions has also been attempted using RT-PCR, but this has not been successful because of the highly variable nature of gene fusions. In the case of EML4-ALK4, at least 20 different fusions result in the activated tyrosine kinase. Another difficulty with RT-PCR is the amount and quality of genetic material from tumor tissue, e.g., in formalin fixed paraffin embedded (FFPE) form. See, e.g., Liu et al. (2015) PLoSOne 10: e0117032.
Because detection is time and resource intensive, the testing rate is relatively low. Cancers associated with ALK fusions are very sensitive to ALK inhibitors such as crizotinib and ceretinib. Gene fusions with Rearranged during Transcription (RET), such as with KIF5B or CCDC6, are also sensitive to therapy, e.g., with vandetanib (see Matsubara et al. (2007) J. Thorac. Oncol. 7:1872). The low rate of testing for gene fusions thus represents a great lost opportunity for treatment.